Alzheimer's disease (AD) is the mostcommoncause of dementia inthe elderly. Inthe U.S., this disease affects approximately 3-4 million persons, costing the U.S. economy more than $50 billion peryear. The cause(s) of this debilitating neurodegenerative disease is (are) presently unknown. However,a large body of evidence indicates that at least some, if not all, AD cases are due to genetic factors. Genetic analysis of families with multiple casesof early-onset AD has shownthat 3 autosomal dominantgenesare responsible for atleastsome occurrences of the disease. Inthesefamilies, offspring of affected personsare at least at 50% risk of inheriting a familial ad (FAD)gene and developing AD. Late-onset FAD(LOFAD) appearsto involve othergenes andisa more complex disease. Using linkage analysis, other sophisticated statistical genetic methods, and positional cloning approaches, the long-range goal of this project is to identifythe underlying causes of AD by identifying the genes responsible for genetic forms of late-onset AD. Using genetic linkage analysis based on Monte Carlo MarkovChain methods, we identified a quantitative trait locus on chromosome 19p13.2 that affectsAD risk. This locus wasidentifiedasaquantitative trait thataffects age-of-onset. The 19p locus targeted by this project is distinct from ApoE, another LOFADgene located at 19q13. To identify this new LOFADgene by positional cloning, the following steps will be performed. First, a physical, sequence, and gene map of 19p13.2 spanning the region indicated by linkage analysis will be generated. Second, genes in this region will be screened for polymorphic sites bydatabase analysis and DMA sequence analysis. Third, polymorphisms spanning the region will beusedto testfor linkage disequilibrium in the region. Polymorphic sites tested will include short tandem repeatpolymorphic sites and single nudeotide polymorphism (SNP) sites. Fourth, SNP's in genes in the region will betested as pathogenic sites in multiple familial and case-control samples to identify the true pathogenic allele. Fifth, when the gene and pathogenic alleles are found, functional assayswill bedevised to determine the mechanism of pathogenesis leading toAD. Identification of additional LOFADgenes should greatly enhance our understanding ofADandpotentially leadto new tvDes of therapies. PERFORMANCE SfTEtS) (organization, city, states) ; . Veterans Affairs Puget Sound Health CareSystem,Seattle Division; 1660S. Columbian Way, Seattle, WA98108 (an affiliate hospital of the University of Washington): Phone (206) 764-2701; FAX (206) 764-2569 University of Washington, Seattle, WA KEY PERSONNEL Seeinstructionson Page 11. Usecontinuation pagesasneededto provide the reo^i^ irrfbrmatwn inthefomtf shown below. Name Organization Role on Project C i/Schellenberg, Gerard D., Ph.D. CVBird, Thomas D., M.D. CVWijsman, E. M., Ph.D. [unreadable] l/Yu,Chang-En, Ph.D. VeteransAffairs Puget Sound Health Care System P.I. VeteransAffairs Puget SoundHealth Care System co-P.I. University of Washington co-P.I. Veterans Affairs Puget Sound Health Care System -co-P.I. PHS398 (Rev. 4/98) Page 2 BB Number pages consecutively atthe bottom throughout the application.Dono*usesuffixes such as3a,3b. CC Prin^^Pivestigator/Program Director (Last, first, middle): Sc^^Pnberg, Gerard David Type the name of the principal investigator/program director at the top of each printed page and each continuation page. (For type specifications, see instructions on pages.) RESEARCHGRANT TABLE OF CONTENTS Page Numbers Face Page _ .-. '. _....'. _ 1 Description,